9-132912317-G-T

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 2P and 1B. PM2BP4

The NM_000368.5(TSC1):​c.878C>A​(p.Thr293Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a benign outcome for this variant. 12/21 in silico tools predict a benign outcome for this variant. No clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar.

Frequency

Genomes: not found (cov: 32)

Consequence

TSC1
NM_000368.5 missense

Scores

1
8
10

Clinical Significance

Not reported in ClinVar

Conservation

PhyloP100: 2.98
Variant links:
Genes affected
TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]

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ACMG classification

Classification made for transcript

Verdict is Uncertain_significance. Variant got 1 ACMG points.

PM2
Very rare variant in population databases, with high coverage;
BP4
Computational evidence support a benign effect (MetaRNN=0.3630528).

Transcripts

RefSeq

Gene Transcript HGVSc HGVSp Effect Exon rank MANE Protein UniProt
TSC1NM_000368.5 linkc.878C>A p.Thr293Asn missense_variant Exon 9 of 23 ENST00000298552.9 NP_000359.1 Q92574-1Q86WV8X5D9D2

Ensembl

Gene Transcript HGVSc HGVSp Effect Exon rank TSL MANE Protein Appris UniProt
TSC1ENST00000298552.9 linkc.878C>A p.Thr293Asn missense_variant Exon 9 of 23 1 NM_000368.5 ENSP00000298552.3 Q92574-1
TSC1ENST00000490179.4 linkc.878C>A p.Thr293Asn missense_variant Exon 10 of 24 3 ENSP00000495533.2 A0A2R8Y6S8

Frequencies

GnomAD3 genomes
Cov.:
32
GnomAD4 exome
Cov.:
31
GnomAD4 genome
Cov.:
32

ClinVar

Not reported in ClinVar

Computational scores

Source: dbNSFP v4.3

Name
Calibrated prediction
Score
Prediction
AlphaMissense
Benign
0.088
BayesDel_addAF
Uncertain
0.079
D
BayesDel_noAF
Benign
-0.12
CADD
Benign
20
DANN
Uncertain
0.99
DEOGEN2
Uncertain
0.46
T;.;T;.;T;.;T;.;.;.;.;.;.;.;.;.;.;T;.
Eigen
Benign
0.057
Eigen_PC
Benign
0.14
FATHMM_MKL
Pathogenic
0.98
D
LIST_S2
Benign
0.79
.;T;T;T;.;.;.;T;T;.;T;.;.;T;T;T;T;T;T
M_CAP
Benign
0.083
D
MetaRNN
Benign
0.36
T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T;T
MetaSVM
Uncertain
0.56
D
MutationAssessor
Uncertain
2.2
M;.;M;.;M;.;M;.;.;.;.;.;.;.;.;.;.;.;.
PrimateAI
Benign
0.34
T
PROVEAN
Benign
-0.86
N;N;N;.;.;.;.;.;.;.;.;.;.;.;.;.;.;N;.
REVEL
Uncertain
0.30
Sift
Uncertain
0.024
D;D;D;.;.;.;.;.;.;.;.;.;.;.;.;.;.;D;.
Sift4G
Uncertain
0.051
T;T;T;.;.;.;.;.;.;.;.;.;.;.;.;.;.;T;.
Polyphen
0.0030
B;.;B;.;B;.;B;.;.;.;.;B;B;B;.;.;.;B;.
Vest4
0.16
MutPred
0.52
Loss of glycosylation at T293 (P = 0.0129);.;Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);.;.;Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);Loss of glycosylation at T293 (P = 0.0129);.;Loss of glycosylation at T293 (P = 0.0129);.;
MVP
0.74
MPC
0.58
ClinPred
0.88
D
GERP RS
4.9
Varity_R
0.11
gMVP
0.33

Splicing

Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
0.0
Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

No publications associated with this variant yet.

Other links and lift over

hg19: chr9-135787704; API